Alzheimer's disease (AD) dementia currently afflicts over 5 million people in the United States and is projected to rise to 11-16 million elderly by the year 2050. Although aging is the most important risk factor for AD, it remains unclear to what extent the molecular changes that underlie 'normal' age-associated memory deficits contribute to symptoms of dementia observed in patients with AD. Recently my colleagues and I demonstrated that spatial memory deficits in mouse models of aging and AD correspond to disruption of Ca2+-dependent plasticity in neurons of the hippocampus. Albeit similar, the magnitude of neuronal dysfunction and scope of memory deficits were exacerbated in AD mice. The present proposal seeks to address whether 'normal' aging and AD-related memory impairments in these mouse models result from disruption of common molecular pathways, or result from divergent molecular alterations that confer similar cellular phenotypes. In order to do this, the applicant requires additional supervised research training in proteomics and gene transduction systems under the direction of primary mentor Dr. Andrew Greene (Professor of Physiology and Director of a National Center for Proteomics Research and Development at MCW) and co-mentor Dr. Nashaat Gerges (Assistant Professor, Molecular, Cell Biology and Anatomy at MCW). The central goal of this proposal is to assist the Principal Investigator establish her independence and secure a tenure-track faculty position such that she can lead a major research program aimed at determining susceptibility and causal factors that underlie aging-related dementias. The Mentored Phase will provide the applicant with training in proteomics to identify and quantitate membrane proteins differentially expressed in the hippocampus of 'normal' aging and AD mice with memory deficits. She will also gain expertise using viral-based gene transduction techniques to validate the role of several de novo 'hits' in memory function, as well as determine their role in modulating intrinsic neuronal excitability and synaptic plasticity. During this phase, the candidate will gain further experience using viral-based gene transduction techniques to attempt the rescue of memory deficits in mouse models of 'normal' aging and AD by downregulating our a priori target TRPC3. The training agenda incorporates laboratory-based training at MCW, opportunities for specialty training in external laboratories, formal coursework, proteomics and AD journal clubs, seminars, and tutorials. Such multidisciplinary training will ensure her ability to design, perform, troubleshoot and interpret experiments at multiple, complementary levels of analysis. The training environment will provide numerous opportunities for career development through national research presentations, collaborations, mentoring students, and training on the responsible conduct of research. During the Independent phase, the applicant will apply her recent training to validate the role of several novel targets in memory function, determine the mechanism/s underlying targeted disruption of memory at the cellular/synaptic level, and attempt to rescue memory deficits in mouse models of 'normal' aging and AD. Because Ab42 levels are strongly correlated with AD-related memory deficits2, we expect that successful rescue of memory deficits may also reduce Ab42 levels that will be tested in collaboration with Alzheimer's Disease expert Dr. Robert Vassar at Northwestern University Medical School. Outcomes of the proposed research have the potential to make a major impact on the identification of new treatments for both aging and AD-related memory disorders. PUBLIC HEALTH RELEVANCE: The significance of this project is that it will employ a novel approach to identify new molecules that contribute to memory deficits that occur in 'normal' aging and Alzheimer's Disease, and use gene therapy approaches to treat memory failure in mouse models of aging and Alzheimer's Disease. Outcomes of the proposed research have great potential to make a major impact on the identification of new treatments for both age-associated cognitive decline and Alzheimer's Disease dementia.